Project Abstract 70-80% of metastatic breast cancer patients suffer from bone metastasis, and bone is the most frequent first site of metastasis. A characteristic feature of these metastases is their osteolytic nature, which causes remarkable bone loss, severe pain, fractures, vertebral collapse, hypercalcemia, and other detrimental effects. Standard treatment for bone metastasis involves the use of anti-osteoclastic agents, such as intravenous bisphosphonates or the anti-RANKL antibody denosumab. Osteoclasts are resident, macrophage-derived cells that resorb bone. They are key mediators of bone remodeling along with osteoblasts, which are mesenchymal cells that form new bone. Bisphosphonates and denosumab function by blocking osteoclast survival, differentiation, and activity, which reduces bone loss. However, even with these drugs, ~40% of patients with breast cancer bone metastases will have a skeletal-related event, such as bone fracture, within a 2-year period, and these drugs have not improved overall survival of metastatic breast cancer patients. We recently discovered that, in bone metastases, RON kinase becomes activated in resident osteoclasts, where it causes bone destruction through a mechanism that is independent of previously known pathways such as RANKL. Genetic knockout of RON kinase, or blocking RON activity with various RON inhibitors, eliminated cancer- mediated bone destruction in several mouse models. Furthermore, administration of a RON kinase inhibitor altered markers of bone turnover in a first-in-human clinical cancer study, indicating potential for treating bone metastasis at safe doses in cancer patients. We propose to test a RON kinase inhibitor, merestinib, in an exploratory Phase IB trial in breast cancer patients with bone metastasis. The primary objectives of the study are (1) to assess the safety and tolerability of merestinib in combination with standard breast cancer therapies in metastatic patients, and (2) to measure the change in bone turnover markers after 12 weeks of investigational therapy. Secondary objectives are to assess (a) bone pain scores, (b) time to skeletal-related events, (c) time to detection of new metastasis in bone or any other site, and (d) effects on other detectable metastases by RECIST criteria. Exploratory objectives are to measure (e) immune activation markers in blood, and (f) correlation between MSP expression in the tumor and effects on bone turnover markers. This will be the first clinical trial testing a RON inhibitor in breast cancer, and results from this small, pioneering study may be a gateway for more detailed clinical investigation of RON inhibitors in metastatic breast cancer patients.